Tarmo P. Roosild, Ph.D. (troosild@nvcancer.org)
Assistant Member, Drug Development Division
Dr. Roosild earned his B.A. in Biochemistry and Cellular Biology with summa cum laude honors from the University of California, San Diego. Following graduation, he completed a five-year tour of duty as a lieutenant in the United States Navy's Nuclear Submarine Force, including certification by the Department of Energy as a Nuclear Engineer. Dr. Roosild returned to UCSD to earn his Ph.D. in Structural Biochemistry. His postdoctoral fellowship was conducted at the Salk Institute for Biological Studies where he was a member of their National Cancer Institute-designated Cancer Center. His research there culminated in the discovery of a novel protein called Mistic, which has been acknowledged by Chemical & Engineering News, the journal of the American Chemical Society, as one of the top four breakthroughs in the field of biochemistry in 2005 (read "Chemistry Highlights 2005"). Dr. Roosild joined the Nevada Cancer Institute's Division of Drug Development in 2006.
Dr. Roosild's research focus is on the structure elucidation of membrane proteins that underlie the molecular processes of neoplastic transformation, metastases, and cell proliferation, as well as the structure-based design of novel therapeutic agents to target these proteins. His laboratory uses x-ray crystallography, in combination with biochemical and biophysical assays, to determine the structural mechanisms by which these critical molecules lead to carcinogenesis and to thus uncover new approaches to cancer treatment.
Laboratory Members
Samantha Castronovo (scastronovo@nvcancer.org)
Adelbert Villoso (avilloso@nvcancer.org)
Research Interests
Our laboratory focuses on problems related to carcinogenesis in protein structure, biochemistry and biophysics with an emphasis on membrane proteins. Our understanding of membrane proteins has significantly lagged that of their soluble counterparts due to the numerous difficulties that arise when trying to analyze this class of proteins with conventional biophysical techniques. Arguably, the most acute of these obstacles is in fact simply producing these proteins in sufficient quantities for structural analysis. Most human and, more generally, eukaryotic membrane proteins cannot be expressed in traditional recombinant systems. Our work has led to the discovery of a protein named Mistic that circumvents this primary bottleneck. When fused to a target protein of interest, Mistic acts analogously to a “super-signal sequence,†facilitating the expression of a variety of membrane proteins in their membrane-integrated conformations within the lipid bilayer of recombinant E. coli bacteria. We continue to develop this technology to extend its application to an increasingly diverse array of proteins by surmounting technical difficulties that exist due to steric and topological restrictions imposed by the planar nature of the lipid membrane.
Mistic is having a major impact on the field of membrane protein structural biology allowing the study of certain scientific problems that were until recently intractable. We are applying this technology to the study of human mitochondrial proteins involved in the regulation of apoptosis. The committing step toward initiation of mitochondrial-mediated apoptosis is the release of cytochrome C from the mitochondria into the cytoplasm, a process that is strictly regulated by several membrane-integrated proteins. Predominant among these are the Bcl-2 family of apoptotic regulators. These proteins have been extensively structurally characterized in their inactive, soluble conformations, but perform their primary function after integrating into the outer mitochondrial membrane, having transitioned into an alternative conformation that remains virtually uncharacterized and controversial. We also focus on several integral membrane proteins that reside permanently within the outer mitochondrial membrane (such as MtCH2), for which evidence is accumulating that they may act as receptors for the Bcl-2 proteins, mediating their conformational rearrangements and intermolecular interactions.
Publications
Roosild, T.P., Castronovo, S., Miller, S., Choe, S. and Booth, I.R. (2007) Structure
of the Kef channel-regulating enzyme. In preparation.
Roosild, T. P., Castronovo, S. and Choe, S. (2006) Structure of anti-FLAG M2 Fab
domain and its use in the stabilization of engineered membrane proteins. Acta
Cryst., F62. Online pub. August 18, 2006.
Roosild, T. P., Vega, M., Castronovo, S. and Choe, S. (2006) Characterization of
the family of Mistic homologues. BMC Structural Biology, 6, 10. Online pub.
May 16, 2006.
Roosild, T. P. and Choe, S. (2005) Redesigning an integral membrane K+ channel
into a soluble protein. Protein Engineering, Design & Selection, 18, 79-84.
Online pub. March 23, 2005.
Roosild, T. P., Greenwald, J., Vega, M., Castronovo, S., Riek, R., Choe, S. (2005)
NMR structure of Mistic, a membrane-integrating protein for membrane protei
expression. Science, 307, 1317-1321.
Roosild, T. P., Lê, K.-T., Choe, S. (2004) Cytoplasmic gatekeepers of K+ channel
flux: a structural perspective. Trends in Biochemical Sciences, 29, 39-45.
Choe, S. and Roosild, T. (2002) Regulation of K channels by cytoplasmic domains.
Biopolymers, 66, 294-299.
Roosild, T. P., Miller, S., Booth, I., Choe, S. (2002) A mechanism of regulating
transmembrane potassium flux by a ligand-mediated switch. Cell, 109, 781-
791.
Pohl, E., Goranson-Siekierke J., Choi M. K., Roosild, T., Holmes, R. K., Hol, W. G.
J. (2001) Structures of three diphtheria toxin repressor (DtxR) variants with
decreased repressor activity. Acta Crystallographica, D57, 619-27.
Online pub. April 24, 2001.
Biggin, P., Roosild, T., Choe, S. (2000) Potassium channel structure: domain by
domain. Current Opinion in Structural Biology, 10, 456-61.
Structures Solved
KefC-CTD/KefF complex, 2.4Ã…, using an engineered fusion protein that retains
enzymatic activity
Mistic, a membrane-associated protein, by multi-dimensional NMR with site-
selective paramagnetic probing
Fab domain of FLAG M2 monoclonal antibody, 1.85Ã…, phased by molecular
replacement
KTN domain of B. subtilis KtrA, 2.8Ã…, phased by seleno-methionine incorporation,
MAD data collection
KTN domain of M. jannaschii KtrA, 2.3Ã…, phased by osmium derivatization, MAD
data collection
Bcl-xl apoptosis regulator (at acidic pH), 2.5Ã…, phased by molecular replacement
Diphtheria toxin repressor (Cys102Ser mutant), 2.3Ã…, phased by molecular
replacement
Patents
Compositions and Methods for Producing Recombinant Proteins.
U. S. Patent Application 20060211087, September 21, 2006; U. S.
Provisional Application No. 60/639,174, December 22, 2004.
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